Prostaglandin e1, f1, and a1 analogs

ABSTRACT

THIS INVENTION IS A GROUP OF PROSTAGLANDIN E1, F1 AND A1 ANALOGS WHICH DIFFER FROM THE NATURAL COMPOUNDS IN HAVING ONE OR MORE ALKYL OF FLUORO SUBSTITUENTS NEAR THE END OF THE CARBOXYLIC ACID CHAIN. THESE COMPOUNDS ARE USEFUL FOR THE SAM PHARMACOLOGICAL PURPOSES AS THE NATURAL COMPOUNDS.

United States Patent O 3,767,695 PROSTAGLANDIN E F AND A ANALOGS John E. Pike and William P. Schneider, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich.

No Drawing. Continuation-impart of abandoned application Ser. No. 748,167, July 29, 1968. This application Sept. 22, 1971, Ser. No. 182,872

Int. Cl. C07c 61/36, 69/74 US. Cl. 260-468 D 38 Claims ABSTRACT OF THE DISCLOSURE This invention is a group of prostaglandin E F and A analogs which differ from the natural compounds in having one or more alkyl of fiuoro substituents near the end of the carboxylic acid chain. These compounds are use ful for the same pharmacological purposes as the natural compounds.

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of my copending application Ser. No. 748,167, filed July 29, 1968, now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to compositions of matter and to methods for making and using them. In particular, this invention relates to novel analogs of PGE PGF PGF PGA and their salts and esters.

PGE has the following structure:

W cuoH Prostaglandin F (PGF has the following structure:

Prostaglandin A (PGA has the following structure:

PGE PGF tPGF and PGA are derivatives of prostanoic acid which has the following structure and atom numbering:

,IWQOOH Various isomers of PGB PGF PGF and PGA, are known. For example, the compound of the following structure is known as 8li-PGE or 8-iso-PGE Patented Oct. 23, 1973 p CC Also, the compound of the following structure is known as 15/3-PGE although l5R-PGE and 15-epi-PGE are alternative names for this compound.

In the formulas above as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The configuration of the hydroxy at C-15 in PGE PGF PGF and PGA is Salthough alpha is preferred as a designation for that configuration. The configuration of the hydroxy at C-15 in lSfi-PGE represented by the formula immediately above, is R although beta is preferred as a designation for that configuration. See Nature 212, 38 (1966) for discussion of the configuration of the prostaglandins.

Each of the novel PGE PGF !PGF and PGA analogs of this invention is encompassed by one of the following formulas:

Compounds of Formulas I and IV are of the PGE type. Compounds of Formulas II and V are of the PGF type. Compounds of Formulas III and VI are of the PGA -type.

In Formulas I to VI, R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the fi-position with 3 chloro, 2 or 3 bromo, or one, 2, or 3 iodo. Also in Formulas I to VI, indicates attachment of the group to the ring in alpha or beta configuration, m is 2 to 6, and p is l to 7. In Formulas I, II, and III, Z is ethylene substituted with one or 2 fluoro, i.e., --CH CHF, CHFCH CH CF CF CH or -CHFCHF-. In Formulas IV, V, and VI, Z is ethylene substituted with one or 2 methyl or ethyl i.e.,

Also included among the novel PGE PGF PGF,,, and PGA, anlogs of this invention are the pharmacologically acceptable salts of the compounds of Formulas I to V1 wherein R is hydrogen.

The PGE -type compounds of Formulas I and IV are useful for pharmacological and medicinal purposes as will be described hereinafter. These same compounds are also useful as intermediates for the preparation of the corresponding compounds of the PGF ,,-type, the PGF,,- type, and the PGA -type.

Formulas I to VI are intended to include compounds wherein the side chain hydroxy has the same configuration as in F613,, i.e., alpha (S), and compounds wherein the side chain hydroxy has the opposite configuration, i.e., beta (R or epi). In all of these compounds, the carboncarbon double bond in the side chain is in trans configuration and that side chain is attached to the cyclopentane ring in beta configuration, both as shown in those formulas.

With regard to the novel PGE type, PGF ,-type, PGF -type, and PGA -type analogs of Formulas I to VI, examples of alkyl of one to 8 carbon atoms, inclusive, are methyl, ethyl, propyl, octyl, and isomeric forms thereof, e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, Z-methylpentyl, methylhexyl, Z-ethylhexyl, 4,4-dimethylpentyl, and the like. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl, Z-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, Z-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, S-tert-butylcyclopentyl, cyclohexyl, 4-tertbutylcyclohexyl, 3-isopropylcyclohexyl, 2,2 dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, l-phenylethyl, Z-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and I-(Z-naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, ochlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethyiphenyl, 4-chloro-2-rnethylphenyl, and 2,4-dichloro-3-methylphenyl.

PGE PGF PGF and PGA and their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses, For that reason,

butyl, pentyl, hexyl, heptyl, r

these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of PGE PGF and PGA; as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for PGF Stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE and PGA as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-toglass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially, PGE are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dosage range of about 10 g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

PGE, and PGA are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 g. to about 500 g. per kg. of body Weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

PGE PGA PGF and PGF are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.004 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

PGE PGA PGF and PGF are especially useful as additives to blood, blood products, blood substitutes.

and other fluids which are used in artificial exracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about .001 to mg. per liter of circulating fluid. It is especially useful to use these compounds, in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

PGE is extremely potent in causing stimulation of smooth muscle, and is also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore 'PGE is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, PGE is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

PGE PGA and PGF are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 g. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 ,ug. per kg. of body weight total per day.

As mentioned above, PGE is a potent antagonist of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGE PGF and PGA compounds are useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insuffiation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of body Weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these prostaglaudins can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophyllin); and corticosteroids (ACTH and precinisolone). Regarding use of these compounds, see South African Pat. No. 681,055.

The PGE PGA and PGF compounds also increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. Therefore, these compounds are useful in managing cases of renal disfunction, especially those involving blockage of the renal vascular bed. Illustratively, the compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 pg. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The PGF PGF PGE and PGA compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGF for example, is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approxi mately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

The novel compounds of this invention encompassed by Formulas I to VI each cause the same biological re sponses described above for the known prostaglandins. Each of these compounds is accordingly useful for the above-described pharmacological uses, and is used for those purposes as described above. However, it is preferred not to use the compounds of Formulas I to VI wherein R is ethyl substituted in the fi-position with chloro, bromo, or iodo for these pharmacological purposes. Those compounds are more useful for other purposes as will be described hereinafter.

The natural prostaglandins, PGE PGF and PGA and the PGE, reduction product PGF are all potent in causing multiple biological responses even at low doses. For example, PG E is extremely potent in causing vasodepression and smooth muscle stimulation, and also is potent as an antilipolytic agent. In striking contrast, the novel Formulas I to VI compounds are substantially more specific with regard to potency in causing prostaglandinlike biological responses. Therefore, each of the Formulas I to V1 compounds is surprisingly and unexpectedly more useful than one of the corresponding known prostaglandins for at least one of the pharmacological purposes indicated for the latter, and is surprisingly and unexpectedly more useful for that purpose because it has a different and narrower spectrum of activity than the natural prostaglandi-n, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than when the natural prostaglandin is used for the same purpose. Moreover, some of these novel prostaglandin analogs have greater potency in causing one or more of the above-described biological responses than the corresponding natural compound.

Further, these novel Formulas I to VI prostaglandin analogs are especially useful because they have a substantially longer duration of activity than the corresponding known compounds, and because they can be administered orally, sublingually, intravaginally, or rectally, as well as by the usual intravenous, intramuscular, or subcutaneous injection or infusion as indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

Especially preferred compounds for the abovedescribed pharmacological purposes are those within the scope of Formulas I to VI wherein p is 4, i.e., wherein (CH represents tetramethylene. Another preference is that m be 4, i.e., that --(CH be tetramethylene. Two other preferences regarding Formulas I to V1 are that either the -(CH ),,,Z-COOR, or the side chain be attached to the ring in alpha configuration and that the side-chain hydroxy have the same configuration as in PGE i.e., the alpha configuration.

The novel prostaglandin analogs of Formulas I to VI,

including the preferred compounds defined above, are

used for the above-described pharmacological purposes in the free acid form, i.e., when R, is hydrogen, in the ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester can be any of those within the above definition of R except that as mentioned above, use of the compounds wherein R is ethyl substituted in the ,8-position with chloro, bromo, or iodo for these purposes is not preferred. Among the various esters, alkyl of one to four carbon atoms, inclusive, are preferred. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these Formulas I to VI compounds are those with cations which are quaternary ammonium ions, or the cationic form of a metal, ammonia, or an amine.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations within the scope R, are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N methylhexylamine, decylami-ne, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, u-phenylethylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2- methylpyrrolidine, 1,4 dimethylpiperazine, 2 methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups. e.g., mono-, diand triethanolamine, ethyldiethanolamine, N-butylethanolamine, Z-amino-l-butanol, 2 amine-2-ethyl-l,3-propanediol, 2-amino-2-methyl l propanol, tris(hydroxymethyl)aminoethane, N-phenylethanolamine, N (p-tertamylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosarnine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations within the scope of R are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of Formulas I to VI are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, sublingually, topically, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased Water solubility that R be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixers, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

As mentioned above, the PGE -type compounds of Formulas I and IV are used as intermediates to prepare the corresponding PGF -type, and PGF -type compounds of Formulas II and V, and PGA -type compounds of Formulas III and VI.

The PGF ,-type and PGF ,-type compounds are prepared by carbonyl reduction of the corresponding PGE- type compounds. For example, carbonyl reduction of a Formula I PGE -type compound gives a mixture of the corresponding Formula II PGF -type and PGF -type compounds. Similarly, carbonyl reduction of a Formula IV PGE -type compound gives a mixture of the corresponding Formula V PGF ,-type and PGF -type compounds.

These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostanoic acid derivatives. See, for example, Bergstrom et al., Arkiv Kemi 19, 5 63 (1963), Acta Chem. Scand. 16, 969 (1962), and British specification No. 1,097,533. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium(tri-tert-butoxy)aluminum hydride, the metal borohydrides, especially sodium, potassium and zinc borohydrides, the metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostanoic acid derivatives. See, for example, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965 and Gren et al., J. Lipid Research 5, 117 (1964). Especially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, and countercurrent distribution procedures.

The PGA -type compounds are prepared by acidic dehydration of the corresponding PGE -type compounds. For example, acidic dehydration of a Formula I PGE type compound gives the corresponding Formula III PGA -type compound. Similarly, acidic dehydration of a Formula IV PGE -type compound gives the corresponding Formula VI PGA -type compound.

These acidic dehydrations are carried out by methods known in the art for acidic dehydrations of known prostanoic acid derivatives. See, for example, Pike et al., Proc. Nobel Symposium II, Stockholm (1966), Interscicnce Publishers, New York, pp. 162-163 (1967); and British specification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especially acetic acid, are preferred acids for this acidic dehydration. Dilute aqueous solutions of mineral acids, e.g., hydrochloric acid, especially in the presence of a solubilizing diluent, e.g., tetrahydrofuran, are also useful as reagents for this acidic dehydration, although these reagents may cause partial hydrolysis of an ester reactant.

These carbonyl reductions and acidic dehydrations are shown in Chart A for Formula I PGE -type reactants and Formula II PGF -type (11,) and PGF -type (II,,) and Formula III PGA -type products. Similar processes are used for transformation of Formula IV PGE -type reactants to the corresponding PGF ,type, PGF -type and PGA -type products. In Chart A, m, p, R Z, and are as defined above.

CHART A o twg -z-coom o (mag a-coon,

an no The PGE -type esters encompassed by Formula I are prepared by the sequence of reactions shown in Chart B. Similar reaction sequences are used to prepare the PGE type esters of Formula IV. In Chart B, m, p, and Z are as defined above, and R has the same definition as R except that hydrogen is not included in the definition of R R is alkyl of one to 5 carbon atoms, inclusive, and indicates alpha or beta attachment of to the cyclopentane ring and exo or endo configuration with respect to the group attached to the cyclopropane ring. The PGE -type acids of Formula I (R is hydrogen) are not prepared by this Chart B sequence, but rather from certain of the Formula I-A esters by methods described below.

Exo-bicyclo[3.1.0]hexane olefins of Formula VII have the formula:

VII-A These olefins are known in the art or are prepared by methods known in the art. See, for example, Belgian Pat. No. 702,477; reprinted in Farmdoc Complete Specifications, Book 714, No. 30,905, page 313, Mar. 12, 1968. See also Just et al., J. Am. Chem. Soc. 91, 5364 (1969).

In that Belgian patent, the reaction sequence leading to exo olefin VII-A is as follows: The hydroxy of 3-cyclopentenol is protected, for example, with a tetrahydropyranyl group. Then a diazoacetic acid ester is added to the double bond to give anexo-endo mixture of a bicyclo [3.1.0]hexane substituted at 3 with the protected hydroxy 10 and at 6 with an esterified carboxyl. The exo-endo mixture is treated with a base to isomerize the endo isomer in the mixture to more of the exo isomer. Next, the carboxylate ester group at 6 is transformed to an aldehyde group. Then, said aldehyde group is transformed by the Wittig reaction to a moiety of the formula This moiety is in exo configuration relative to the bicyclo ring structure. Next, the protective group is removed to regenerate the 3-hydroxy which is then oxidized, for example, by the Jones reagent, to give an intermediate of the formula:

Finally, this Formula X intermediate is alkylated with an w-iOdO or w-bfOIIlO ester of the Formula I Endo-bicyclo[3.l.OJhexane olefins of Formula VII have the formula:

(cHzlm-z-coos H (VIIB These are prepared by reacting endo-bicyclol3.l.OJhex-Z- ene-6-carboxylic acid methyl ester with diborane in a mixture of tetrahydrofuran and diethyl ether to give a mixture of the methyl esters of endo-bicyclo[3.l.0] hexan-3-ol-6-carboxylic acid and endo-bicyclo[ 3.1.0] hexan-2-ol-6-carboxylic acid. This mixture is reacted with dihydropyran to give the corresponding mixture of tetrahydropyranyl ethers. The carboxylate group at 6 in this mixture of ethers is then transformed to an aldehyde group which in turn is transformed by the Wittig reaction to a moiety of the formula CH=CH(CH -CH This moiety is in endo configuration relative to the bicyclo ring structure. Next, the tetrahydropyranyl group is removed, and the resulting hydroxy group is oxidized, for example, by the Jones reagent, to give an intermediate of the formula:

CH=CH- (CH -CH Mixed with this Formula XI intermediate is some of the corresponding Z-keto isomer. These are separated by silica gel chromatography, and the Formula XI compound is alkylated with a compound of Formula I or Br-(CH -Z-COOR The resulting alpha and beta isomers of Formula VIIB are then separated as described above for the Formula VII-A exo olefins.

Four stereoisomers are possible for each of the exo and endo olefins encompassed by Formulas VIIA and VIIB. The CH=CH moiety can exist in cis or trans form, and and the CH Z-COOR chain can be attached to the cyclopentane ring in alpha or beta configuration.

The Wittig reaction leading to the intermediates of Formulas X and XI produces mixtures of cis and trans isomers, with the cis isomer usually predominate. These isomers can be separated, for example, by silica gel chromatography, and alkylated separately to give cis and trans forms of the Formula VII-A and VII-B olefins. However, these cis and trans olefins are equally useful as intermediates in the processes of Chart B, and there is usually no need to carry out this separation.

The alkylation reactions leading from exo intermediate X to exo olefin VII-A and from endo intermediate XI to endo olefin VIIB produce mixtures of alpha and beta isomers. The processes of Chart B usually do not change this alpha or beta configuration of the moiety, and when the pure alpha or pure beta isomers of the Formula I-A PGE -type product is desired, it is necessary to separate alpha and beta isomers at some stage, i.e., olefin VII, glycol VIII, bis-sulfonate IX, or product IA. Separation of alpha and beta isomers of olefin VII is preferred. This separation is carried out by silica gel chromatography as described in said Belgian patent and exemplified below.

With regard to the Wittig reagents necessary to prepare the intermediates of Formulas X and XI, these are triphenylphosphonium bromides prepared as known in the art from the corresponding normal C -to-C alkyl bromides, all of which are known in the art or can be prepared by methods known in the art.

The necessary alkylating agents for the above-described alkylations of the exo and endo intermediates X and XI to form the corresponding compounds of Formulas VII-A and VII-B are represented by the formulas and Hal(CH XCOOR wherein m, R X and Z are as defined above and Hal is iodo or bromo. These esters of substituted w-iodo or w-bromo alkanoic acids are known in the art or are prepared by methods known in the art. For example, they are prepared starting with the appropriate succinic acid, HOOCZ-COOH or HOOCXCOOH, wherein Z and X are as defined above, all of which are known in the art. These succinic acids are transformed to anhydrides by methods known in the art. The anhydride is then reacted with an alcohol or a phenol of the formula R OI-I, wherein R is as defined above, by methods known in the art, to give a mixture of isomeric half esters,

plus R OOCZ-COOH or HOOCXCOOR plus R OOCXCOOH. These isomers are separated. Then, the free carboxyl is transformed to -COCl with thionyl chloride, the COCl is transformed to CH0 by the Rosenmund reduction, the CH0 is transformed to CH OH by reduction with sodium borohydride, and the CH OH is transformed to CH Br by reaction with phosphorus tribromide, thereby producing and R OOCXCH Br. Then, additional CH moieties are added as often as desired by replacing Br with CN using sodium cyanide, hydrolyzing -CN to COOH, and transforming COOH to CI-I Br as described above. Finally, -Br is replaced with I if desired by reaction of the bromoester with sodium iodide in acetone.

Referring again to Chart B, the glycol intermediates of Formula VIII are prepared by hydroxylation of olefins VII. Hydroxylation reagents and procedures for this purpose are known in the art. See, for example, Gunston, Advances in Organic Chemistry, vol. 1, pp. 103-147 (1960), Interscience Publishers, New York, NY. Especially useful hydroxylation reagents for this purpose are osmium tetroxide and performic acid (formic acid plus hydrogen peroxide). Various mixtures of glycols isomeric with respect to the CH(OH)CH(OH)- moiety are obtained by these olefin hydroxylations depending on the nature of the hydroxylation reagent and the cis and trans content of the Formula VII olefin. These glycol isomers can be separated by silica gel chromatography. However, these separations are usually not necessary since all isomers of a particular glycol are equally useful as intermediates to produce the desired Formula I-A product.

Referring again to Chart B, the glycol intermediates of Formula VIII are transformed to bis-alkanesulfonates of Formula IX by reaction of the glycol with an alkanesulfonyl chloride or bromide, the alkane portion of which contains one to 5 carbon atoms, inclusive. The reaction is carried out in the presence of a base to neutralize the by product acid. Especially suitable bases are tertiary amines, e.g., dimethylaniline or pyridine. It is usually sufficient merely to mix the two reactants and the base, and maintain the mixture in the range to 25 C. for several hours. The Formula IX bis-sulfonic acid esters are then isolated by procedures known to the art and exemplified below. It is usually not necessary to purify the bis-sulfonic acid esters prior to transformations to the desired PGE -type esters.

Referring again to Chart B, the bis-sulfonic acid esters of Formula D( are transformed to the desired PGE -type esters of Formula I-A by reacting the bis-sulfonic acid ester with water. This reaction is carried out by mixing the bis-sulfonic acid ester with water in the range about 0 to about 60 C. In making dl-2,2-dimethyl- PGE methyl ester, 25 C. is a suitable reaction temperature, the reaction then proceeding to completion in about 20 hours. It is advantageous to have a homogeneous reaction mixture. This is accomplished by adding sufiicient of a water-soluble organic diluent which does not enter into the reaction. Acetone is a suitable diluent. The desired product is isolated by evaporation of excess water and diluent if one is used. The residue contains a mixture of Formula I-A isomers which differ in the configuration of the side chain hydroxy, being either a (S) or B (R). These are separated from by-products and from each other by silica gel chromatography.

For this transformation of a Formula IX bis-sulfonate to a Formula I-A PGE -type product, it is preferred to use the bis-mesyl esters, i.e., compounds of Formula IX wherein both R are methyl.

As mentioned above, the processes of Chart B lead to esters of PGE -type compounds. For some of the pharmacological uses described above, it is preferred that the PGE -type compound be in free acid form, or in salt from which requires the free acid as starting material. Moreover, for some of the pharmacological uses described above, Formula II or V PGF -type compounds of Formula HI or VI PGA -type compounds in free acid form or salt form are preferred. Formulas II and V PGF -type esters are easily saponified to free acids by procedures known in the art. However, it is difiicult to hydrolyze or saponify the PGE -type esters or the PGA -type esters to free acids without unwanted structural changes in the desired acids. When a Formula I or IV PGE -type free acid (R is hydrogen) is desired, an ester wherein R (R is ethyl substituted in the beta-position with 3 chloro, 2 or 3 bromo, or one, 2, or 3 iodo is used as a starting material. Such esters, for example, wherein R (R is -CH CC1 are transformed to free acids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid. Zinc dust is preferred as the physical form of the zinc. Mixing the halo ester with the zinc dust at about 25 C. for several hours in the presence of the alkanoic acid causes replacement of the haloethyl moiety with hydrogen. The free acid is then isolated from the reaction mixture by procedures known in the art and exemplified below. For preparation of the free acids of Formulas I and IV in this manner, the B,B, 8-trichloroethyl esters are preferred. This same procedure is also used to prepare PGF P6P and PGA -type free acids (R is hydrogen), starting with the corresponding haloethyl ester. However, as mentioned above, this procedure is not necesary to prepare PGF -typeacids.

These Formula I and IV haloethyl esters, i.e., wherein R is ethyl substituted in the beta-position with 3 chloro, 2 or 3 bromo, or one, 2, or 3 iodo, are prepared in several ways. Some of these are outlined in Chart C. The haloethyl esters are also prepared by alkylation of a Formula X exo intermediate or a Formula XI eudo intermediate with the haloethyl esters of the w-bromo or w-iOdO alkanoic acid.

Chart C describes the transformation of a Formula VII olefin ester other than a haloethyl ester to haloethyl esters of a Formula VIII glycol. Thus, Chart C relates only to PGE -type products of Formula I, as does Chart B. However, as for Chart B, similar reactions are available CHART C oqicoolh H0 D-COOR;

CH=CH-A CH=CH-A (VII-C) (XII) HO O-COO-haloethyl H0 o-coou CH=CH-A CH=CH-A (XIV) leading to the PGE -type products of Formula IV. In Chart C, Formula VII-C is the same as Formula VII (Chart B) except that haloethyl esters are not included in VII-C. In other words, R, has the same definition as R except that R, does not include ethyl substituted in the beta-position with 3 chloro, 2 or 3 iodo, or one, 2, or 3 iodo. Also in Chart C, is as defined above, A is -(CH CH wherein p is as defined above, and D is (CH -Z wherein m and Z are as defined above.

To make the desired Formula VIII-A haloester, it is necessary at some stage to saponify the COOR moiety to -COOH and then esterify that with the appropriate haloethanol, e.g., CCI CH OH. Formula VII-C olefin esters and Formula VIII glycol esters each have a ring carbonyl group adjacent to the point of attachment of -DCOOR to the ring. Saponification of such a keto esther is likely to lead to isomerization such that an alpha-attached chain will change partly to a betaattached chain, and a beta partly to an alpha. Therefore, keto ester VII-C is reduced, for example, with sodium borohydride according to known procedures described above and exemplified below, to hydroxy ester XII. This hydroxy ester is then saponified to hydroxy acid XIII, also by known procedures.

Three reactions are necessary to transform hydroxy acid XIII to keto glycol haloester VIII-A. The ring hydroxy is oxidized back to a ring carbonyl, the carboxyl is esterified with a haloethanol, and the -CH=CH is hydroxylated to CH(OH)CH(OH. As shown in Chart C, these three reactions are carried out in any of three sequences, i.e., XIII to XIV to XV to VIII-A, XIH to XVI to XV to VIII-A, and XIII to XVI to XVII to VIII-A. Of these, the first is preferred.

For the oxidation of XIII to XVI or XIV to XV, an especially useful reagent is the Jones reagent, i.e., acidic chromic acid. See J. Chem. Soc. 39 (1946). Acetone is a suitable diluent for this purpose, and a slight excess of oxidant and temperatures at least as low as about 0 C., preferably about 10 to about 20 C. should be used.

The oxidation proceeds rapidly and is usually complete in about 5 to about 30 minutes. Excess oxidant is destroyed, for example, by addition of a lower alkanol, advantageously isopropyl alcohol, and the aldehyde is isolated by conventional methods, for example, by extraction with a suitable solvent, e.g., diethyl ether. Other oxidizing agents can also be used. Examples are mixtures of chromium trioxide and pyridine or mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, I. Am. Chem. Soc. 87, 5661 (1965).

For the esterification to haloethyl esters XIV, XV, or VIII-A, the acid is reacted with the appropriate haloethanol, e.g., 5,5,,6-trichloroethanol, in the presence of a carbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g., pyridine, preferably in the presence of an inert liquid diluent, e.g., dichloromethane, for several hours at about C.

The PGE PGF PGF and PGA -type free acids of Formulas I to VI are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be gnerally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alaknol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

Molecules of each of the compounds encompassed by the formulas of PGE PGF PGF PGA 818PGE l5B-PGE I-IX, and XII to XVII each have at least one center of asymmetry, and each can exist in racemic form and in either enantiomeric form, i.e., d and l. A formula accurately defining the d form would be the mirror image of the formula which defined the 1 form. Both formulas are necessary to define accurately the corresponding racemic form. For convenience, the various formulas herein and in the claims are to be construed as including racemic (d1), d, and 1 compounds. However, for the above-described pharmacological purposes, preferred compounds are the racemic compounds of Formulas I to V1 and the optically active enantiomers of these compounds with the same absolute configuration as the PGE obtained from certain mammalian tissues, for example, sheep vesicular glands and human seminal plasma, or compounds obtained by carbonyl reduction or acid dehydration of a compound so obtained. The specific com- 16 pounds shown above in the formulas of PGE PGF PGF and PGA are intended to represent that absolute configuration. See Nature 212, 38 (1966).

Hereinafter, names of specific final products of Formulas I to VI will be based on relationship to optically active PGE Substituents and structural variations will be based on the numbering of the formula of prostanoic acid; thus, for example, 2,2-dimethyl-PGE or Z-fluoro- PGA An alpha or S configuration of the hydroxy at 0-15 will be assumed unless 15,8 appears before the name. An alpha configuration at C-8 will also be assumed unless 86 appears before the name. An optically active compound with the same absolute configuration of PGE will be assumed unless dl (racemic) or cut (optically active unnatural configuration) appear before the name.

When an optically active (d or 1) final compound is desired, that is made by resolution of the racemic compound or by resolution of one of the asymmetric racemic intermediates. These resolutions are carried out by procedures known in the art. For example, when a final compound or an asymmetric intermediate is a free acid, the dl form thereof is resolved into the d and 1 forms by reacting said free acid by known general procedures with an optically active base, e.g., brucine or strychnine, to give a mixture of two diastereoisomers which are separated by known general procedures, e.g., fractional crystallization, to give the separate diastereoisomeric salts. The optically active acid is then obtained by treatment of the salt with an acid by known general procedures.

Alternatively, exo or endo bicyclo[3.l.0]hexane olefin reactants VII or XVI are transformed to ketals with an optically active 1,2-glycol, e.g., D() 2,3-butanediol, by reaction of said 1,2glyco1 with the olefin in the presence of a strong acid, e.g., p-toluenesulfonic acid. The resulting ketal is a mixture of diastereoisomers which is separated into the cl and l diastereoisomers, each of which is then hydrolyzed with an acid, e.g. oxalic acid, to the original keto compound, now in optically active form. These reactions involving optically active glycols and ketals for resolution purposes are generally known in the art. See, for example, Chem. Ind. 1664 (1961) and J. Am. Chem. Soc. 84, 2938 (1962). Dithiols may be used instead of glycols.

The invention can be more fully understood by the following examples and preparations.

All temperatures are in degrees centigrade.

Brine as used herein referes to saturated aqueous sodium chloride solution.

The collection of chromatographic eluate fractions starts when the eluant front reaches the bottom of the column.

Preparation 1 .Endo-bicyclo [3 1.0] hexan-3-olfi-carboxylic acid methyl ester A mixture of endo-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid methyl ester (103 g.) and anhydrous diethyl ether (650 ml.) is stirred under nitrogen and cooled to -5 C. A one molar solution (284 ml.) of diborane in tetrah'ydrofuran is added dropwise during 30 minutes While keeping the temperature below 0' C. The resulting mixture is then stirred and allowed to warm to 25 C. during 3 hours. Evaporation under reduced pressure gives a residue which is dissolved in 650 ml. of anhydrous diethyl ether. The solution is cooled to 0 C., and 3 N aqueous sodium hydroxide solution (172 ml.) is added dropwise under nitrogen with vigorous stirring during 15 minutes, keeping the temperature at 0 to 5 C. Next, 30% aqueous hydrogen peroxide (94 ml.) is added dropwise with stirring during 30 minutes at 0" to 5 C. The resulting mixture is stirred an hour while warming to 25 C. Then, 500 ml. of brine is added, and the diethyl ether layer is separated. The aqueous layer is washed with four ZOO-ml. portions of ethyl acetate, the washings being added to the diethyl ether layer, which is then washed with brine,

dried, and evaporated to give 115 g. of a residue. This residue is distilled under reduced pressure to give 69 g. of a mixture of the methyl esters of endo-bicyclo[3.l.0] hexan-3-ol-6-carboxylic acid and endobicyclo[3.l.0]hexan-2-ol-6-carboxylic acid; B.P. 8695 C. at 0.5 mm.

Preparation 2.Endo-bicyclo [3 l .0] hexan-3 -ol-6-carboxylic acid methyl ester tetrahydropyranyl ether The 2-01 and 3-o1 mixture (66 g.) obtained according to Preparation 1 in 66 ml. of dihydropyran is stirred and cooled at 15-20 C. during addition of 3 m1. of anhydrous diethyl ether saturatedwith hydrogen chloride. The temperature of the mixture is then kept in the range 20 to 30 C. for one hour with cooling, and is then kept at 25 for 15 hours. Evaporation gives a residue which is distilled under reduced pressure to give 66 g. of a mixture of the methyl esters-tetrahydropyranyl ethers of endo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic acid and endo-bicyclo[3.1.0]hexan-2-ol-6-carboxylic acid; B.P. 96-104 C. at 0.1 mm.

Preparation 3 .Endo-6-hydroxymethylbicyclo[3 1 .0] hexan-3-ol 3-tetrahydropyranyl ether A solution of the mixture (66 g.) of products obtained according to Preparation 2 in 300 ml. of anhydrous diethyl ether is added dropwise during 45 minutes to a stirred and cooled mixture of lithium aluminum hydride (21 g.) in 1300 ml. of anhydrous diethyl ether under nitrogen. The resulting mixture is stirred 2 hours at 25 C., and is then cooled to C. Ethyl acetate (71 ml.) is added, and the mixture is stirred 15 minutes. Water (235 ml.) is then added, and the diethyl ether layer is separated. The water layer is washed twice with diethyl ether and twice with ethyl acetate. A solution of Rochelle salts is added to the aqueous layer, which is then saturated with sodium chloride and extracted twice with ethyl acetate. All diethyl ether and ethyl acetate solutions are combined, washed with brine, dried, and separated to give 61 g. of a mixture of the 3-tetrahydropyranyl ethers of endo-6-hydroxymethylbicyclo 3. 1 .0] hexan-3-ol and endo-6-hydroxymethylbicyclo[3.1.0]hexan-2-ol.

Preparation 4.Endo-bicyclo [3 .1.0] hexan-3-ol-6-carboxaldehyde 3-tetrahydropyranyl other A solution of the mixture (34 g.) of products obtained according to Preparation 3 in 1000 ml. of acetone is cooled to 10 C. Jones reagent (75 m1. of a solution of 21 g. of chromic anhydride, 60 ml. of water, and 17 ml. of concentrated sulfuric acid), precooled to 0 C., is added dropwise with stirring during 10 minutes at 10 C. After 10 minutes of additional stirring at l0 C., isopropyl alcohol (35 ml.) is added during 5 minutes, and stirring is continued for minutes. The reaction mixture is then poured into 8 l. of an ice and water mixture. The resulting mixture is extracted 6 times with dichloromethane. The combined extracts are washed with aqueous sodium bicarbonate solution, dried, and evaporated to give 27 g. of a mixture of the tetrahydropyranyl ethers of endo-bicyclo- [3.l.0]hexan 3 ol-6-carboxaldehyde and endo-bicyclo- [3.1.0]hexan-Z-ol-6-carboxaldehyde.

Preparation 5 .Endo-6( l-heptenyl) -bicyclo [3 1 .0] hexan-3-ol tetrahydropyranyl ether A mixture of hexyl bromide (100 g.), triphenylphosphine (160 g.), and toluene (300 ml.) is stirred and heated at reflux for 7 hours. The mixture is then cooled to 10 C., and the crystals which separate are collected by filtration, washed with toluene, and dried to give 147 g. of hexyltriphenylphosphonium bromide; MP. 197- 200 C.

A mixture of hexyltriphenylphosphonium bromide (102 g.) and benzene (1200 ml.) is stirred under nitrogen during addition of a solution of butyl lithium in hexane (146 ml. of a solution, w./v.). The resulting mixture is stirred 30 minutes. Then a solution of the mixture (27 Preparation 6.-Endo-6-( 1-hepteny1)-bicyclo[3 .1 .0] hexan-3-ol Oxalic acid (3 g.) is added to a solution of the mixture (58 g.) of products obtained according to Preparation 5 in 1500 ml. of methanol. The mixture is heated under reflux with stirring for 1.5 hours. Evaporation under reduced pressure gives an oil which is dissolved in dichloromethane. That solution is washed with aqueous sodium bicarbonate solution, dried, and evaporated under reduced pressure. The residue is dissolved in an isomeric hexane mixture (Skellysolve B), and chromatographed on 600 g. of wet-packed silica gel. The column is eluted with 2 l. of Skellysolve B, and then successively with 1 l. of 2.5%, 2 l. of 5%, 21. of 7.5%, 5 l. of 10%, and 31. of 15% ethyl acetate in Skellysolve B. Concentration of the combined fractions corresponding to the 10% and 15% ethyl acetate gives 16 g. of a mixture of endo 6-(1- heptenyl)-bicyclo[3.1.0]hexan 3 01 and endo 6 (1- heptenyl) -bicyclo [3 .1 .0] hexan-2-ol.

Preparation 7.-Endo-6- l-heptenyl )-bicyclo [3 l .0] hexan-3-one A solution of the mixture (15 g.) of products obtained according to Preparation 6 in 450 ml. of acetone is cooled to l0 C. and stirred While adding 30 ml. of Jones reagent (Preparation 4) dropwise during 10 minutes. The resulting mixture is stirred 10 minutes at l0 C. Then, isopropyl alcohol (15 ml.) is added, and stirring is continued for 10 minutes. The mixture is poured into 2400 ml. of water. The Water is extracted 5 times with dichloromethane. The combined extracts are washed with aqueous sodium bicarbonate solution, dried, and concentrated to give an oil. The oil is chromatographed on 500 g. of silica gel wet-packed with isomeric hexanes (Skellysolve B), eluting successively with 2 l. of Skellysolve B, 2 l. of 2.5% ethyl acetate in Skellysolve B, and 10 l. of 5% ethyl acetate in Skellysolve B. The first 1.5 l. of the 5% ethyl acetate in Skellysolve B eluate is concentrated to give 5.9 g. of endo-6-(1-heptenyl)bicyclo[3.1.0]hexan- 3-one; R 0.62 on thin layer chromatography with silica gel plates developed with 20% ethyl acetate in cyclohexane.

Following the procedures of Preparations 5, 6, and 7, but using in place of the hexyl bromide in Preparation 5, propyl bromide, butyl bromide, pentyl bromide, heptyl bromide, octyl bromide, and nonyl bromide, there are obtained the l-butenyl, l-pentenyl, 1-hexenyl, l-octenyl, 1- nonenyl, and l-decenyl endo compounds, respectively, corresponding to the l-heptenyl endo product of Preparation 7.

Also following the procedures of Preparations 5, 6, and 7, but using in place of the endo-bicyclo[3.1.0]hexan-3- ol-6-carboxaldehyde 3 tetrahydropyranyl ether, reactant of Preparation 5, the corresponding exo compound, prepared as described in said Belgian Pat. No. 702,477, there are obtained l-butenyl, l-pentenyl, l-h'exenyl, l-heptenyl, l-octenyl, l-nonenyl, and l-decenyl exo compounds corresponding to the above-defined endo products of Preparation 7.

Example 1.dl 2,2-dimethyl-PGE methyl ester and d1 15p-2,2-dimethyl-PGE methyl ester (A) A solution of endo-6-(l-heptenyl)-bicyclo[3.1.0]- 3-one (Preparation 7, 6.33 g.) and 14.6 g. of methyl 19 7-iodo-2,2-dimethylheptanoate in 200 ml. of tetrahydrofuran is stirred at 25 C. under nitrogen. A solution of 3.8 g. of potassium tert-butoxide in 800 ml. of tetrahydrofuran is added slowly over a 45 minute period. Then, 70 ml. of 5% hydrochloric acid is added, followed by 5 ml. of pyridine. The mixture is concentrated under reduced pressure to remove most of the tetrahydrofuran, and then is diluted with 200 ml. of ice water. The mixture is extracted with two ZOO-ml. portions of 3:1 ether-dichloromethane. The ether-dichloromethane solution is washed successively with dilute hydrochloric acid, water, dilute aqueous sodium thiosulfate, and brine. The washed solution is dried over sodium sulfate and concentrated under reduced pressure to give 16.9 g. of oil. The oil is chromatographed over 1.5 kg. of silica gel packed wet with 2% methanol in dichloromethane. The column is eluted with 6 l. of dichloromethane, 6 I. of 1%, and 6 l. of 2% methanol in dichloromethane, taking 300-1111. fractions. Fractions 25 to 36 are combined and concentrated to give 4.25 g. of methyl 6-endo-(l-heptenyl)-3ox0bicyclo- [3 1.0] hexane-21x- (2,2-dimethylheptanoate) The corresponding beta compound is obtained from subsequent eluate fractions.

(B) A solution of 10.38 g. of methyl 6-endo-(1-heptenyl)-3-oxobicyclo[3.1 .0] hexane 2a (2,2-dimethylheptanoate) (obtained according to A above) in 250 ml. of tetrahydrofuran is warmed to 50 C. and stirred. Osmium tetroxide (0.5 g.) is added. Then, a warm solution of 8.5 g. of potassium chlorate in 100 ml. of water is added and the mixture is stirred at 50 C. for 2 hours and 40 minutes. The mixture is concentrated by distillation under reduced pressure to remove most of the tetrahydrofuran. The aqueous residue is extracted with dichloromethane. The dichloromethane extract is washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give 14.1 g. of an oil. The oil is chromatographed over 1400 g. of silica gel wet packed in 1:1 ethyl acetate-cyclohexane. The column is eluted with 1:1 ethyl acetate-cyclohexane, taking 200-ml. fractions. Fractions 20 to 45 are combined and concentrated to give 7.3 g. of methyl 6-endo-(1,2-dihydroxyheptyl)-3- oxobicyclo[3.1.0] hexane-2:1- 2,2-dimethylheptanoate) (C) A solution of 8.07 g. of methyl 6-endo-(l,2-dihydroxyheptyl) 3 xobicyclo[3.1.0] hexane 20c (2,2-dimethylheptanoate) (obtained according to B above) in 100 ml. of pyridine is stirred under nitrogen and cooled in an ice bath while 10.0 ml. of methanesulfonyl chloride is added dropwise over about 15 minutes. The mixture is stirred 2.5 hours at 0 C.; then ml. of water is added dropwise while keeping the temperature below 5 C. The mixture is diluted with 100 g. of ice and extracted with 1:3 dichloromethane-ether. The dichloromethane-ether extract is washed with ice-cold dilute hydrochloric acid (100 ml. conc. hydrochloric acid mixed with 400 ml. of ice and water), aqueous sodium bicarbonate, and brine, dried over sodium sulfate and concentrated under reduced pressure to give 10.2 g. of oil. The oil is dissolved in 300 ml. of acetone and diluted, with stirring, with 150 ml. of water. The mixture is allowed to stand at 25 C. for about 20 hours; then it is diluted with 300 ml. of water and concentrated under reduced pressure until most of the acetone is removed, and extracted with 1:3 dichloromethane-ether mixture. The dichloromethane-ether solution is washed successively with dilute aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure to give 10.0 g. of oil. The oil is chromatographed over 1300 g. of silica gel wetpacked in 1:1 ethyl acetate-cyclohexane. The column is eluted with 8.5 l. of 2:1 ethyl acetate-cyclohexane, 2 l. of and 2.5 l. of methanol in ethyl acetate, taking 100-ml. portions. Fractions 84 to 106 are combined and concentrated to give 1.18 g. of d1 15fi-2,2-dimethyl-PGE methyl ester; mass spectral peaks at 396, 378 and 360; infrared absorption at 3420, 1730, 1320, 1250, 1195, 1150, 1075, 102.5, and 970 CULTI- 20 Fractions 116 to are combined and concentrated to give 1.48 g. of dl 2,2-dimethyl-PGE methyl ester; mass spectral peaks at 396, 378 and 360; infrared absorption at 3390, 1730, 1320, 1250, 1195, 1150, 1075, 1020 and 970 cmf Example 2.--dl 3,3-dimethyl-PGE methyl ester and dl 15B-3,3-dimethyl-PGE methyl ester Following the procedure of Example 1, part A, but using methyl 7-iodo-3,3-dimethylheptanoate in place of methyl 7-iodo 2,2-dimethylheptanoate, there are obtained methyl 6-endo-(1 heptenyl) 3 oxobicyclo[3.1.0]hex ane-2e-(3,3-dimethylheptanoate) and methyl 6-endo-(lheptenyl) 3 oxobicyc1o[3.1.0]hexane-2B-(3,3-dimethylheptanoate), separated by silica gel chromatography, eluting with a 1025% ether-Skellysolve B gradient.

Following the procedure of Example 1, part B, methyl 6-endo (1 heptenyl) 3 oxobicyclo[3.1.0]hexane-2e- (3,3 dimethylheptanoate) is transformed to methyl 6-endo-(1,2-dihydroxyheptyl) 3 oxobicyclo[3.l.0]hexane-2a- 3,3-dirnethylheptanoate Following the procedure of Example 1, part C, methyl 6-endo-(1,2-dihydroxyheptyl) 3 oxobicyclo[3.1.0]hexane-2a-(3,3-dimethylheptanoate) is transformed to dl 3,3- dimethyl-PGE methyl ester, M.P. 3738 C.; mass spectral peaks at 396, 378, 360, 325, 307 and 293; infrared absorption at 3400, 1740, 1325, 1230, 1150, 1130, 1075, 1015 and 965 cmr and d1 15B-3,3-dimethyl-PGE methyl ester; mass spectral peaks at 396, 378, 360, 347, 346, 325, 307 and 293; infrared absorption at 3420, 1735, 1330, 1230, l1l35, 1075, 1015 and 970 CHLTI. These products are separated by silica gel chromatography, elutmg successively with 50% ethyl acetate-Skellysolve B (2 1.), a gradient of 50100% ethyl acetate in Skellysolve B (24 1.), and a gradient of 0-10% methanol in ethyl acetate (2 1.).

Example 3.dl 8p-3,3-dimethyl-PGE methyl ester and (11 8 3,15 fi-3,3-dimethyl-PGE methyl ester Following the procedures of Example 1, parts B and C, methyl 6-endo-( 1-heptenyl)-3-oxobicyclo [3.1.0]hexane-ZB-(3,3-dimethylheptanoate) from Example 2 is transformed to dl 8;3-3,3-dimethyl-PGE methyl ester and dl 8fi,15;3-3,3-dimethyl-PGE methyl ester.

Example 4.dl 2-fluoro-PGE methyl ester and d1 15fl2-fiuoro-PGE methyl ester Following the procedure of Example l-A but using methyl 7-iodo-2-fluoroheptanoate in place of methyl 7-iodo-2,Z-dimethylheptanoate, there are obtained methyl 6-endo-(1-heptenyl) 3 oxobicyclo[3.1.0]hexane-2a-(2- fiuoroheptanoate) and methyl 6-endo-(1-heptenyl)-3-oxob1cyclo[3 .1 .0] -hexane-25- (2-fluoroheptanoate) Following the procedures of Example 1, parts B and C, methyl 6-endo-(1-heptenyl)-3-oxobicyclo[3.1.0]hexane-Za-(Z-fluoroheptanoate) is transformed to dl 2-fiuoro- PGE methyl ester and dl ISfi-Z-liuoro-PGE methyl ester.

Example 5.dl 8,8-2-flu0ro-PGE methyl ester and d1 SpJSfi-Z-fiuoro-PGE methyl ester Following the procedures of Example 1, parts B and C, methyl 6-endo-(l-heptenyl)-3-oxobicyclo[3.1.0]hexane-2,8-(2-fiu0roheptanoate) from Example 4 is transformed to dl SB-Z-fluoro-PGE, methyl ester and d1 85, l5fi-2-fluoro-PGE methyl ester.

Following the procedures of Examples 1-5 but using exo starting materials rather than endo starting materials, the same PGE -t-ype methyl esters are obtained.

Also following the procedures of Examples 1-5 but using separately as reactants the ethyl, Z-ethylhexyl, phenyl, benzyl, cyclohexyl, and 5,5,,8-trichloroethyl esters of the various substituted 7-iodoheptanoic acids in place of the methyl esters, there are obtained the 8oL-15oc, 80:- 15 3, 8 9-15, and 8,6- forms of the corresponding esters 21 of d1 2,2-dimethyl-PGE dl 3,3-dimethyl-PGE and 2- fluoro-PGE Also following the procedures of Examples 1-5 but using separately as reactants both optically active enantiomers of the methyl, ethyl, 2-ethylhexyl, phenyl, benzyl, cyclohexyl, and 5,13,,8-trichloroethyl esters of the various 6-endo-(substituted-1-alkenyl)-3-ox0bicyclo[3.1. ]hexane-2-heptanoic acid reactants defined in those examples, there are obtained the sot-15oz, 8a-15fl, 818-1501, and 85-1519 forms of the coresponding esters of 3,3-dimethyl-PGE ent 3,3-dimethyl-PGE 2fluoro-PGE and cut 2-fluoro-PGE Also following the procedures of Examples 1-5 but using in place of the endo-6-(l-heptenyl)-bicyclo[3.1.0] hexan-3-one reactant, the corresponding l-butenyl, 1- pentenyl, l-hexenyl, l-ocetenyl, l-nonenyl, and ldecenyl compounds, there are obtained the methyl, ethyl, 2-ethylhexyl, phenyl, benzyl, cyclohexyl, and 5,18,}3-trichloroethyl esters of the racemic and both optically active enantiomer forms of the corresponding analogs of 2,2-dimethyl-PGE 3,3-dimethyl-PGE and 2-fluoro-PGE Also following the procedures of Preparations 5-7 and Example 1, but using as pairs of reactants in place of the hexyl bromide of Preparation 5 and the methyl 7- iodo-2,Z-dimethylheptanoate of Example 1, the corresponding racemic and optically active PGE -type esters are produced:

wherein R is methyl, ethyl, 2-ethylhexyl, phenyl, benzyl, cyclohexyl, or e,;8,fl-trichloroethyl.

Example 6.-dl 3,3-dimethyl-PGE and d1 l5fi-3,3-dimethyl-PGE (A) A solution of sodium borohydride (7.8 g.) in 40 ml. of water is added to a solution of methyl 6-endo- (1-heptenyl)-3-oxobicyclo[3.1.0]hexane-2a-(3,3 dimethylheptanoate) (16.3 g.) in 400 ml. of isopropyl alcohol at 0 C. The resulting mixture is stirred 2.5 hours at 0 C. Then, 25 ml. of acetone is added to the mixture. After minutes of stirring, the mixture is acidified with dilute aqueous acetic acid and concentrated under reduced pressure at 45 C. to remove isopropyl alcohol. The residue is diluted with water and extracted with ethyl acetate. The extract is washed successively with water and brine, dried with sodium sulfate, and evaporated under reduced pressure to give 16.4 g. of methyl 6-endo- (l-heptenyl)-3-hydroxybicyclo[3.1.0]hexane 2a-(3,3-dimethylheptanoate (B) The product from A (16.4 g.) is dissolved in 400 ml. of methanol, and the solution is purged of air 'by bubbling nitrogen through the solution for 5 minutes.

Then, 50 ml. of 45% aqueous potassium hydroxide solu- 22 tion, also purged of air in like manner, is added to the solution, and the mixture is maintained at 25 C. under nitrogen for 24 hours. Water (1500 ml.) is then added, and the mixture extracted with dichloromethane. The extracted solution is acdified with cold dilute aqueous hydrochloric acid, and then extracted with dichloromethane. This second extract is washed twice with water, once with brine, dried with sodium sulfate, and evaporated under reduced pressure at 40 C. to give 15.4 g. of 6- endo-(l-heptenyl) 3-hydroxybicyclo[3.1.0]hexane 2w (3,3-dimethylheptanoic acid).

(C) A solution of the product from B (6.8 g. and 1,1'-carbonyldiimidazole (3.2 g. in 30 ml. of tetrahydrofuran is maintained 15 minutes at 25 C. fi,;9,fi-trichloroethanol (9' ml. and a trace of potassium tert-butoxide are then added, and the mixture maintained at 25 C. for 20 hours. Diethyl ether (300) ml. is added, and the solution is washed with cold 2% aqueous sodium bicarbonate solution. Then, the solution is washed twice with water, once with brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on 900 g. of silica gel, eluting with 20% ethyl acetate in cyclohexane, collecting ZOO-ml. fractions. Fractions 12-25 are combined and evaporated to give 5.2-3 g. of 3, 3, 3-trichloroethyl 6-endo-(1-heptenyl)-3-hydroxybicyclo [3. 1.0] hexane-2w 3,3-dimethylheptanoate).

(D) Jones reagent (8 ml., see Preparation 4) is added wtih stirring during 30 seconds to a solution of the product from C (5.23 g.) in 190 ml. of acetone at 0 C. The resulting mixture is maintained at 0 for 5 minutes, and then is diluted with ice and water and extracted with dichloromethane. The extract is washed successively with water and brine, dried with sodium sulfate, and evaporated under reduced pressure at 35 C. The residue is chromatographed on 350 g. of silica gel, eluting with 10% ethyl acetate in cyclohexane, collecting 60-ml. fractions. Fractions 6-15 are combined and evaporated to give 3.2 g. of fi,13,}3-trichloroethy1 6-endo-(1- heptenyl)-3-oxobicyclo[3.1.0]hexane-2a (3,3-dimethylheptanoate) (E) Following the procedure of Example 1, part B, the product of D (5.6 g.) is transformed to ,B,B,B-trichloroethyl 6-endo-(1,2 dihydroxyheptyl)-3-oxobicyclo [3.1.0]hexane-2w(3,3-dimethylheptanoate) by treatment with a mixture of osmium tetroxide and potassium chlorate. The product is chromatographed on 600 g. of silica gel, eluting with cyclohexane-ethyl acetate (2-1) for eluate fractions 1-50 and then with cyclohexane-ethyl acetate (1-1) for eluate fractions 51-65, collecting ml. fractions. Fractions 26-65 are combined and evaporated to give 4.15 g. of the desired glycol product.

(F) Following the procedure of Example 1, part C, the glycol product of E (4.15 g.) is transformed to the corresponding bis-mesylate. That is transformed by the procedure of Example 1, part C, to 4.3 g. of a mixture of the B,fi, 3-trichloroethyl esters of dl 3,3-dimethy1-PGE and d1 15fi-3,3-dimethyl-PGE Those are separated by chromatography on 650 g. of silica gel, eluting in 60-ml. fractions as follows: ethyl acetate-cyclohexane (2-1), 50 fractions; 1% methanol in ethyl acetate, 25 fractions; and 20% methanol in ethyl acetate, 16 fractions. Fractions 77-91 are combined and evaporated to give 0.77 g. of dl 3,4-dimethyl-PGE 5,5,,3-trichloroethyl ester. Fractions 46- 65 are combined and evaporated to give a residue which is chromatographed on 150 g. of silica gel, eluting in 30-ml. fractions with ethyl acetate-cyclohexane (2-1). Fractions 8-15 are combined and evaporated to give 0.64 g. of dl l5 S-3,3-dimethyl-PGE fi,B,fi-trichloroethyl ester.

(G) Zinc dust (1.6 g.) is added to a solution of dl 3,3-dimethyl-PGE 5,5,B-trichloroethyl ester (0.397 g.) in 20 ml. of glacial acetic acid. The mixture is stirred 2 hours at 25 C. Then, ml. of ethyl acetate and 100 ml. of 0.1 normal hydrochloric acid are added, and the mixture is stirred. The aqueous layer is separated, and the ethyl acetate layer is extracted with three 200-ml. portions of water.

The combined aqueous extracts are saturated with sodium chloride, and the ethyl acetate which separates is added to the main ethyl acetate solution. The ethyl acetate solution is dried with sodium sulfate and evaporated under re duced pressure at 40 C. The residue is dissolved in 10 ml. of toluene and the solution is evaporated. The residue is again dissolved in toluene and the solution is evaporated. The residue is chromatographed on 65 g. of silica gel (Silicar CC4), eluting in l-ml. fractions as follows: 2% methanol in dichloromethane, 10 fractions; methanol in dichloromethane, fractions; 10% methanol in dichloromethane, fractions. Fractions 27-32 are combined and evaporated to give 0.25 g. of dl 3,3-dimethyl- PGE mass spectral peaks at 364, 346, and 3286.

(H) Following the procedure of G, d] lSB-3,3-dimethyl- PGE ,8,B,B-trichloroethyl ester (0.53 g.) is transformed to dl l5,8-,3,3-dimethyl-PGE The product is chromatographed on 60 g. of silica gel (Silicar CC4), eluting in 15-ml. fractions as follows: 2% methanol in dichloromethane, fractions; 5% methanol in dichloromethane, 20 fractions. Fractions 3340 are combined and eva orated to give 0.16 g. of dl l5B-3,3-dimethyl-PGE mass spectral peaks at 364, 346 and 3285.

Following the procedures of Example 6, but using the appropriate initial racemic or optically active reactant in part A, there are prepared 3,3-dimethyl-PGE ent 3,3-dimethyl-PGE l5 8-3,3-dimethyl-PGE ent 155-3,3-dimethyl-PGE dl 8e-3,3-dimethyl-PGE 8p-3,3-dimethyl- PGE ent 8fi-3,3-dimethyl-PGE dl 8t3,l5fl-3,3-dimethyl- 'PGE 8/3,15fl-3,3-dirnethyl-PGE ent 8fl,155-3,3-dimethyl-PGE dl 2,2-dimethyl-PGE 2,2-dimethyl-PGE ent 2,2-dimethyl-PGE dl 15,8-2,2-dirnethyl-PGE,, 1513-2, 2-dimethyl-PGE ent 15fi-2,2-dimethyl-PGE dl 3-fluoro- PGE 3-fiuoro-PGE ent 3-fiuoro-PGE dl 155-3-fluoro- PGE 15B-3-fiuoro-PGE and ent 15B-3-fiuoro-PGE Also following the procedures of Example 6, each of the PGE -type 5,5,;3-trichloroethyl esters described after Example 5, above, is prepared and transformed to the corresponding PGE -type acid.

Example 7.dl 2,2-dimethyl-PGA methyl ester A solution of 200 mg. of dl 2,2-dimethyl-PGE, methyl ester in a mixture of 2 ml. of tetrahydrofuran and 2 ml. of 0.5 N hydrochloric acid is stirred under nitrogen at C. for 5 days. The reaction mixture is then diluted with brine and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried over sodium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel and eluted with 2060% ethyl acetate in Skellysolve B, then finally ethyl acetate, taking fractions. Those fractions shown by TLC to contain the desired product free of starting material and impurities are combined and concentrated to yield the title compound.

Following the procedure of Example 7, dl 15,8-2,2-dimethyl-PGE methyl ester, and both optically active forms of these 15a and 15B 2,2-dimethyl- PGA compounds are obtained from the corresponding PGE -type ester.

Also following the procedure of Example 7, the free acid and the ethyl, Z-ethylhexyl, phenyl, benzyl and cyclohexyl esters of the 150: and 15,6 forms of the racemic and both optically active forms of 2,2-dimethyl-PGA are obtained from the corresponding PGE -type compounds.

Also following the procedure of Example 7, the free acid and the methyl, ethyl, Z-ethylhexyl, phenyl, benzyl, and cyclohexyl esters of the 80tl5a, 801-1513, 8,8-ll5a, and 85-155 forms of the racemic and both optically active forms of 3,3-dimethyl-PGA and Z-fiuoro-PGA are obtained from the corresponding PGE -type compounds.

Also following the procedure of Example 7, each of the PGE -type esters described after Example 5 and each of the PGE -type acids described after Example 6 is dehydrated to the corresponding PGA -type ester and acid.

Example 8.dl 2,2-dimethyl-PGF methyl ester and d1 2,2-dimethyl-PGF methyl ester A solution of 600 mg. of 11 2,2-dimethyl-PGE methyl ester in 30 ml. of isopropyl alcohol is cooled to 0 C. in an ice bath, and a solution of 300 mg. of sodium borohydride in 6 ml. of water is added. The mixture is stirred in the melting ice bath for 2.5 hours; then the reaction mixture is treated with 1 m1. of acetone, stirring for 10 minutes. Dilute acetic acid is added until the mixture is neutral, and the mixture is concentrated under reduced pressure at 40 C. until most of the isopropyl alcohol and acetone are removed. The residue is diluted with Water and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed over g. of silica gel, wet-packed in 2:1 ethyl acetate-cyclohexane. The column is eluted with 500 ml. of ethyl acetate, 500 ml. of 1%, 500 ml. of 3%, and 500 ml. of 10% methanol in ethyl acetate, taking 25-ml. fractions. Fractions 32-34 are combined and concentrated to give 170 mg. of d1 2,2-dimethyl- PGF methyl ester; M.P. 54-60 (3.; mass spectral peaks at 398, 380, 362, 327 and 3085. Fractions 51 to 65 are combined and concentrated to give 290 mg. of dl 2,2-dimethyl-P6P}, methyl ester, M.P. 69-74 C.; mass spectral peaks at 398, 380, 362, 327 and 3086.

Following the procedure of Example 8, the methyl esters of 2,2-dimethyl-PGE ent 2,2-dimethyl-PGE d1 15,942,2- dimeIhyFPGE l5fi-2,2-dimethyl-PGE and ent IS S-2,2- dimethyl-PGE are each transformed to the corresponding PGF -type and PGF -type methyl esters.

Also following the procedure of Example 8, the free acid and the ethyl, Z-ethylhexyl, phenyl, benzyl, and cyclohexyl esters of the racemic and both optically active forms of 2,2-dimethyl-PGE and 15fi-2,2-dimethyl-PGE are each transformed to the corresponding PGF -type and PGF -type compounds.

Also following the procedure of Example 8, the free acid and the methyl, ethyl, 2-ethylhexy1, phenyl, benzyl, and cyclohexyl esters of the 805-153., 804455, -15(1, and 85-158 forms of the racemic and both optically active forms of 3,3-dimethyl-PGE and 2-fluoro-PGE are each transformed to the corresponding PGF -type and PGF type compounds.

Also following the procedure of Example 8, each of the PGE -type esters described after Example 5 and each of the PGE -type acids described after Example 6 is transformed to the corresponding PGF ,,-type and PGF -type compound.

Example 9.2,2-dimethyl-PGF and dl 2,2-dimethyl- PGF A solution of 200 mg. of d1 2,2-dimethyl-PGF methyl ester in 5 ml. of methanol is mixed with 2.8 ml. of 45% aqueous potassium hydroxide, and the mixture is allowed to stand at 25 C. under nitrogen for about 20 hours. The mixture is diluted with 30 ml. of water and extracted with 15 ml. of ethyl acetate. The aqueous solution is made acid with cold dilute hydrochloric acid and extracted with two 25-ml. portions of ethyl acetate. The ethyl acetate extracts are combined and washed 3 times with water, dried over sodium sulfate, and concentrated to give 182 mg. of crystalline residue. This is recrystallized from an ether-pentane mixture to give 142 mg. d1 2,2- dimethyl-PGF M.P. 1081l2 C.; mass spectral peaks at 384, 366, 348 and 294.

Following the procedure of Example 9 but using (11 2,2-dirnethyl PGF methyl ester in place of d1 2,2-dirnethyl-PGF methyl ester there is obtained d1 2,2-dimethyl-PGF M.P. 102-106 C., mass spectral peaks at 384, 366, 348 and 294.

Following the procedure of Example 9, each of the PGF -type and PGF -type methyl esters described after Example 8 is saponified to the corresponding PGF ,-type and PGF -type acid.

25 We claim: 1. An optically active compound of the absolute configuration of natural PGE or a racemic compound of the formula:

wherein m is 2 to 6 and p is one to 7; wherein R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the fl-position with 3 chloro, 2 or 3 bromo, or one, 2 or 3 iodo; wherein Z is ethylene substituted with one or 2 fluoro; wherein indicates attachment of the group to the ring in alpha or beta configuration; and pharmacologically acceptable salts thereof when R is hydrogen.

2. A compound according to claim 1 wherein R is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and pharmacologically acceptable salts thereof when R is hydrogen.

3. A compound according to claim 1 wherein m is 4.

4. A compound according to claim 1 wherein p is 4.

5. A compound according to claim 2 wherein the formula is I.

6. A compound according to claim 5 wherein the -(CH ZCOOR moiety is attached in alpha configuration.

7. A compound according to claim 6 wherein the sidechain hydroxy is in alpha configuration.

8. A compound according to claim 2 wherein the formula is II.

9. A compound according to claim 8 wherein the -(CH -Z-COOR moiety is attached in alpha configuration.

10. A compound according to claim 9 wherein the ring hydroxy adjacent the -(CH ZCOOR moiety is in alpha configuration.

11. A compound according to claim 9 wherein the ring hydroxy adjacent the -(CH Z-COOR moiety is in beta configuration.

12. A compound according to claim 10 wherein the side-chain hydroxy is in alpha configuration.

13. A compound according to claim 11 wherein the side-chain hydroxy is in alpha configuration.

14. A compound according to claim 2 wherein the formula is 111.

15. A compound according to claim 14 wherein the moiety is attached in alpha configuration.

16. A compound according to claim 15 wherein the side-chain hydroxy is in alpha configuration.

I c c H0 \CHOH- (CH h-CHB wherein R is hydrogen, akyl of one 'to 8 carbon atoms, inclusive cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the fl-position with 3-chloro, 2 or 3 bromo, or one, 2 or 3 iodo; wherein Z is ethylene substituted with one or 2 fluoro; wherein indicates attachment of the group to the ring in alpha or beta configuration; and pharmacologically acceptable salts thereof when R is hydrogen.

18. A compound according to claim 17 wherein R is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and pharmacologically acceptable salts thereof when R is hydrogen.

19. A compound according to claim 18 wherein the formula is I.

20. A compound according to claim 19 wherein the -(CH -ZCOO R moiety is attached in alpha configuration.

21. A compound according to claim 20' wherein the sidechain hydroxy is in alpha configuration.

22. A compound according to claim 21 wherein Z is ethylene substituted by one fluoro.

23. A compound according to claim 21 wherein Z is ethylene substituted by two fluoro on the same carbon atom.

24. A compound according to claim 18 wherein the formula is II.

25. A compound according to claim 24 wherein the (CH ZCOOR moiety is attached in alpha configuration.

26. A compound according to claim 25 wherein the ring hydroxy adjacent the (CH ZCOOR moiety is in alpha configuration.

27. A compound according to claim 25 wherein the ring hydroxy adjacent the (CH ZCOOR moiety is in beta configuration.

28. A compound according to claim 26 wherein the sidechain hydroxy is in alpha configuration.

29. A compound according to claim 27 wherein the side-chain hydroxy is in alpha configuration.

30. A compound according to claim 28 wherein Z is ethylene substituted by one fluoro.

31. A compound according to claim 29 wherein Z is ethylene substituted by one fluoro.

32. A compound according to claim 28 wherein Z is ethylene substituted by two fluoro on the same carbon atom.

33. A compound according to claim 29 wherein Z is ethylene substituted by two fluoro on the same carbon atom.

Z7 Z8 34. A compound to claim 18 wherein the formula is References Cited Green, Biochimica et Biophysica Acta, 231, 419

35. A compound according to claim 34 wherein the (1971). --(CH ZCOOR moiety is attached in alpha congz g d d l 35 h th 5 LORRAINE A. WEINBERGER, Primary Examiner compoun accor mg to c mm W erem e side-chain hydroxy is in alpha configuration. GERSTL Asslstant Exammer 37. A compound according to claim 36 wherein Z is ethylene substituted by one fiuoro. CL

38. A compound according to claim 36 wherein Z is 10 260-211 R 247-2 R, 268 R, 293-65, ethylene substituted by two fluoro on the same carbon 410-9 429-9, 439 R, 456 '68 G, 501.1, atom 501.15, 501.17, 501.2, 514 D, 514 G; 474305, 317

Page l of 2 Pages UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,767,695

. DATED I October 23 l973 |NVENT0R(5) I John E. Pike et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 3, lines 59-60: "Z-pentylcyclopentyl should read:

3-pentylcyclopentyl',

Column l0, lines 68-72: "u-iodo or u-bromo ester of the Formula I -(CH -Z-C00R or Br-(CH -Z-C0OR to give the mixture of the" should read: w-iodo or wbromo ester of the formula l-(CH -Z-C00R or Br-(CH -Z- J C0OR to give a mixture oftwe Column ll lines 40-44: "alkylated with a compound of Formula I -(CH Z-C0OR2 or Br-(CH -Z-C00R The resulting alpha anPI" should read: m alkylated with a compound of the formula l-(CH -Z-C0OR or Br-(CH -Z-C00R The resulting alpha an m Column ll, line 50: "and and the -CH -Z-COOR should read:

-- and the -(CH -Z-cooR2 m Column l3, line 34: m "in salt from should read: in

salt form Column l4, line 36: (XVII) (XVII-A)" should read:

XVII VI I IA a Column 2l lines 37-39: "CH (CH Br" should read: CH (CH Br "CH (CH Br" should read: CH (CH Br --continued on next page-- Page 2 of 2 Pages UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3 ,767 ,695

DATED October 23 1 973 INVENTOR(S) John E. Pike et a] It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Co1umn 21 lines 37-39 (continued) "CH (CH Br" shou1d read: CH (CH )5Br "CH (CH Br" should read: CH (CH Br Signed and Scaled this Twenty-eighth Day of March I978 [SEAL] A nest:

RUTH C. MASON LUTRELLE F. PARKER Arresting Officer Acting Commissioner of Parents and Trademarks 

